Heat-Shock Protein 90 Promotes Nuclear Transport of Herpes Simplex Virus 1 Capsid Protein by Interacting with Acetylated Tubulin

Zhong, Meigong; Zheng, Kai; Chen, Maoyun; Xiang, Yangfei; Jin, Fujun; Ma, Kaiqi; Qiu, Xiangyun; Wang, Qiaoli; Peng, Tao; Kitazato, Kaio; Wang, Yifei

doi:10.1371/journal.pone.0099425

Cited by 45 publications

(47 citation statements)

References 45 publications

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“…Just 30 min after infection, Kaposi's sarcoma-associated herpes virus enhances tubulin acetylation significantly [156]. About 4 h post infection, herpes simplex virus type 1 (HSV-1) increases tubulin acetylation, which in turn enhances HSP90 binding to microtubules and facilitates nuclear localization of viral capsid protein [157]. Notably, this effect is completely opposite from that on NF-AT nuclear localization [150], indicating that tubulin acetylation regulates nuclear import in a context-dependent manner.…”

Section: Tubulin Acetylation In Immune and Viral Responsesmentioning

confidence: 99%

Tubulin acetylation: responsible enzymes, biological functions and human diseases

Yang

2015

Cell. Mol. Life Sci.

213

184

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Microtubules have important functions ranging from maintenance of cell morphology to subcellular transport, cellular signaling, cell migration, and formation of cell polarity. At the organismal level, microtubules are crucial for various biological processes, such as viral entry, inflammation, immunity, learning and memory in mammals. Microtubules are subject to various covalent modifications. One such modification is tubulin acetylation, which is associated with stable microtubules and conserved from protists to humans. In the past three decades, this reversible modification has been studied extensively. In mammals, its level is mainly governed by opposing actions of α-tubulin acetyltransferase 1 (ATAT1) and histone deacetylase 6 (HDAC6). Knockout studies of the mouse enzymes have yielded new insights into biological functions of tubulin acetylation. Abnormal levels of this modification are linked to neurological disorders, cancer, heart diseases and other pathological conditions, thereby yielding important therapeutic implications. This review summarizes related studies and concludes that tubulin acetylation is important for regulating microtubule architecture and maintaining microtubule integrity. Together with detyrosination, glutamylation and other modifications, tubulin acetylation may form a unique 'language' to regulate microtubule structure and function.

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Section: Tubulin Acetylation In Immune and Viral Responsesmentioning

confidence: 99%

Tubulin acetylation: responsible enzymes, biological functions and human diseases

Yang

2015

Cell. Mol. Life Sci.

213

184

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“…Some viruses induce significant acetylation of α-tubulin to stabilize the microtubule cytoskeleton for their intracellular transport by regulating HDAC6, including circovirus, herpes simplex°virus, and influenza A virus (Husain and Harrod, 2011; Zhong et al, 2014; Cao et al, 2015). Recently, HDAC6 has also been reported to be involved in the replication of certain viruses.…”

Section: Discussionmentioning

confidence: 99%

Rabies Virus Infection Induces Microtubule Depolymerization to Facilitate Viral RNA Synthesis by Upregulating HDAC6

Zan

Liu

Sun

et al. 2017

Front. Cell. Infect. Microbiol.

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Rabies virus (RABV) is the cause of rabies, and is associated with severe neurological symptoms, high mortality rate, and a serious threat to human health. Although cellular tubulin has recently been identified to be incorporated into RABV particles, the effects of RABV infection on the microtubule cytoskeleton remain poorly understood. In this study, we show that RABV infection induces microtubule depolymerization as observed by confocal microscopy, which is closely associated with the formation of the filamentous network of the RABV M protein. Depolymerization of microtubules significantly increases viral RNA synthesis, while the polymerization of microtubules notably inhibits viral RNA synthesis and prevents the viral M protein from inducing the formation of the filamentous network. Furthermore, the histone deacetylase 6 (HDAC6) expression level progressively increases during RABV infection, and the inhibition of HDAC6 deacetylase activity significantly decreases viral RNA synthesis. In addition, the expression of viral M protein alone was found to significantly upregulate HDAC6 expression, leading to a substantial reduction in its substrate, acetylated α-tubulin, eventually resulting in microtubule depolymerization. These results demonstrate that HDAC6 plays a positive role in viral transcription and replication by inducing microtubule depolymerization during RABV infection.

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“…HDAC6 exerts its anti-IAV function by negatively regulating the trafficking of viral components via Actub to the host cell plasma membrane [22]. Other studies have shown that herpes simplex virus type 1 (HSV-1), human herpes virus 8 (HHV-8) and adenoviruses enhance microtubule acetylation to facilitate viral proliferation [42–44]. Therefore, we considered that elevated Actub levels might be beneficial for viral proliferation.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Histone Deacetylase 6 Enhances Resistance to Porcine Reproductive and Respiratory Syndrome Virus in Pigs

Song

et al. 2017

PLoS ONE

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Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most economically relevant viral pathogens in pigs and causes substantial losses in the pig industry worldwide each year. At present, PRRSV vaccines do not effectively prevent and control this disease. Consequently, it is necessary to develop new antiviral strategies to compensate for the inefficacy of the available vaccines. Histone deacetylase 6 (HDAC6) is an important member of the histone deacetylase family that is responsible for regulating many important biological processes. Studies have shown that HDAC6 has anti-viral activities during the viral life cycle. However, whether HDAC6 overexpression enhances resistance to PRRSV in pigs remains unknown. In this study, we used a somatic cell cloning method to produce transgenic (TG) pigs that constitutively overexpress porcine HDAC6. These TG pigs showed germ line transmission with continued overexpression of HDAC6. In vitro, virus-challenged porcine alveolar macrophages (PAMs) overexpressed HDAC6, which suppressed viral gene expression and PRRSV production. In vivo, resistance to PRRSV in TG pigs was evaluated by direct or cohabitation mediated infection with a highly pathogenic PRRSV (HP-PRRSV) strain. Compared with non-TG (NTG) siblings, TG pigs showed a significantly lower viral load in the lungs and an extended survival time after infection with HP-PRRSV via intramuscular injection. In the cohabitation study, NTG pigs housed with challenged NTG pigs exhibited significantly worse clinical symptoms than the other three in-contact groups. These results collectively suggest that HDAC6 overexpression enhances resistance to PRRSV infection both in vitro and in vivo. Our findings suggest the potential involvement of HDAC6 in the response to PRRSV, which will facilitate the development of novel therapies for PRRSV.

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Heat-Shock Protein 90 Promotes Nuclear Transport of Herpes Simplex Virus 1 Capsid Protein by Interacting with Acetylated Tubulin

Cited by 45 publications

References 45 publications

Tubulin acetylation: responsible enzymes, biological functions and human diseases

Tubulin acetylation: responsible enzymes, biological functions and human diseases

Rabies Virus Infection Induces Microtubule Depolymerization to Facilitate Viral RNA Synthesis by Upregulating HDAC6

Overexpression of Histone Deacetylase 6 Enhances Resistance to Porcine Reproductive and Respiratory Syndrome Virus in Pigs

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